The mechanisms of drug and hormone action on glycogenolysis, glycogen synthesis, glucose uptake and contractile function will be investigated in skeletal muscle using pharmacogenetic variants carried in inbred strains of mice. These studies will use mice from strains that differ either in their EC50(concentration giving one-half maximum response) or in their maximum response for isoproterenol-stimulated phosphorylase b to a conversion in hemidiaphragms incubated in vitro. The strain differences in isoproterenol-stimulated phosphorylase a formation will be correlated with changes in various steps in the response pathway to study the relative roles of cyclic AMP and Ca2 ion in regulating phosphorylase A formation in mammalian skeletal muscle and to determine the mechanisms of the strain differences. The mechanisms by which B-adrenergic agonists affect glycogen metabolism and contractile function will also be compared in contracting diaphragm muscles from strains differing in isoproterenol responses. The inheritance of the strain differences in drug response will be investigated in breeding studies. These studies will also provide a model system in a mammalian population of the frequency of inherited variations in drug response arising at the target tissue level. The phosphorylase kinase deficiency mutation carried in I strain mice is one variant with a lower maximum isoproterenol-stimulated phosphorylase a formation that has been extensively studied in this laboratory and is one of the few animal models of glycogen storage conditions. The nature of this mutation will be further investigated by purifying and characterizing the mutant phosphorylase kinase, which is present in I strain skeletal muscle in normal amounts. The mechanisms of the increased glucose tolerance and increased muscle glucose uptake in I mice, as compared to other strains, will also be investigated by studying the effects of insulin on glucose uptake, glucose utilization and glycogen synthesis in hemidiaphragms incubated in vitro.